Recovery and Half-Life of von Willebrand Factor-Cleaving Protease after Plasma Therapy in Patients with Thrombotic Thrombocytopenic Purpura

Summary

Plasma exchange using fresh-frozen plasma (FFP) for replacement was given to two brothers during a relapse of thrombotic thrombocytopenic purpura (TTP). A constitutional deficiency of von Willebrand factor(vWF)-cleaving protease had been previously established in both patients. No inhibitor of vWF-cleaving protease was present in patients’ plasmas. They received plasma exchange for four and three consecutive days, respectively. In both patients, the activity of vWF-cleaving protease after the first plasmapheresis session was evaluated and was found to be virtually identical to anticipated activity calculated from predicted patient plasma volume and volume of exchanged plasma. Pathologic platelet counts and lactate dehydrogenase levels were normalized in both patients within 4-6 days. The biologic half-life of vWF-cleaving protease was determined in these patients following the last plasma exchange. The respective half-lives of 3.3 and 2.1 days represent the lowest known clearance rates of proteases in circulating human plasma.

Another patient with relapsing TTP was treated with plasma exchange and/or plasma infusion for 10 consecutive days during the first relapse, 221-231 days after the initial TTP event. Pharmacokinetic studies of vWF-cleaving protease were performed after plasma exchange on day 221 and after plasma infusion on day 231. High level of an IgG in patient plasma, capable of completely inhibiting protease activity in an equal volume of normal plasma, had been established prior to first plasmapheresis. There was no measurable protease activity at any time during plasma therapy. Following plasma exchange, the level of the inhibitor was transiently slightly depressed. After 10 days of plasma therapy, the concentration of the inhibitor in patient plasma was increased about 5-fold. We suggest that, in contrast to protease deficient patients without circulating inhibitor, complementary therapy including immunosuppressive treatment, vincristine and/or splenectomy is indicated in patients with acquired inhibitors of vWF-cleaving protease. Testing for vWF-cleaving protease inhibitor may be useful in predicting the response to plasma exchange in patients with TTP.

• References

• 1 Moake JL, Rudy CK, Troll JH, Weinstein MJ, Colannino NM, Azocar J, Seder RH, Hong SL, Deykin D. Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-5.
• 2 Chow TW, Turner NA, Chintagumpala M, McPherson PD, Nolasco LH, Rice L, Hellums JD, Moake JL. Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura. Am J Hematol 1998; 57: 293-302.
• 3 Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stre-induced platelet aggregation. J Clin Invest 1986; 78: 1456-61.
• 4 Tsai HM, Sussman I I, Nagel RL. Shear stress enhances the proteolysis of von Willebrand factor in normal plasma. Blood 1994; 83: 2171-9.
• 5 Furlan M, Robles R, Lämmle B. Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood 1996; 87: 4223-34.
• 6 Tsai H-M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87: 4235-44.
• 7 Dent JA, Berkowitz SD, Ware J, Kasper CK, Ruggeri ZM. Identification of a cleavage site directing the immunochemical detection of molecular abnormalities in type IIA von Willebrand disease. Proc Natl Acad Sci USA 1990; 87: 6306-10.
• 8 Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lämmle B. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997; 89: 3097-103.
• 9 Furlan M, Robles R, Solenthaler M, Lämmle B. Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura. Blood 1998; 91: 2839-46.
• 10 Byrnes JJ, Khurana M. Treatment of thrombotic thrombocytopenic purpura with plasma. N Engl J Med 1977; 297: 1386-9.
• 11 Shepard KV, Bukowski RM. The treatment of thrombotic thrombocytopenic purpura with exchange transfusions, plasma infusions, and plasma exchange. Semin Hematol 1987; 24: 178-93.
• 12 Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 1916; 17: 863
• 13 Feldschuh J, Enson Y. Prediction of the normal blood volume. Relation of blood volume to body habitus. Circulation 1977; 56: 605-12.
• 14 Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA. and members of the CASG. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med 1991; 325: 393-7.
• 15 Gaddis TG, Guthrie TH, Drew MJ, Sahud M, Howe RB, Mittelman A. Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption. Am J Hematol 1997; 55: 55-8.
• 16 Moake JL, Byrnes JJ, Troll JH, Rudy CK, Hong SL, Weinstein MJ, Colannino NM. Effects of fresh-frozen plasma and its cryosupernatant fraction on von Willebrand factor multimeric forms in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1985; 65: 1232-6.
• 17 Frangos JA, Moake JL, Nolasco L, Phillips MD, McIntite LV. Cryosupernatant regulates accumulation of unusually large vWF multimers from endothelial cells. Am J Physiol 1989; 256: H-1635-44.
• 18 Moake JL. Studies on the pathophysiology of thrombotic thrombocytopenic purpura. Semin Hematol 1997; 34: 83-9.
• 19 Gonias SL, Pizzo SV. Reaction of human α2-macroglobulin half-molecules with plasmin as a probe of protease binding site structure. Biochemistry 1983; 22: 4933-40.
• 20 Seligsohn U, Kasper CK, Østerud B, Rapaport I. S. Activated factor VII: presence in factor IX concentrates and persistence in the circulation after infusion. Blood 1978; 53: 828-37.